KRAS is a key regulatory component in a signaling pathway that involves upstream tyrosine kinase receptors (RTK), including EGFR, and downstream effector pathways regulated by RAF, phosphatidylinositol 3-kinase (PI3K) and Ral-GDS. Activating mutations of the KRAS proto- oncogene are present in ~30% of lung adenocarcinomas and are among the most common oncogenic mutations in human cancers. Although small molecule inhibitors of EGFR and other RTKs show clinical benefit in subsets of lung cancer patients, tumors that harbor KRAS mutations have proven refractory to both targeted and chemotherapeutic approaches, and despite intensive efforts, no effective therapies exist for KRAS mutated lung cancers. Thus, identifying therapeutic strategies to target lung and other human cancers that harbor KRAS mutations remains an important unsolved problem and an area of substantial clinical need. In the previous funding period, we investigated the non-canonical I?B kinase TBK1 as a target in KRAS-driven lung cancers. We elucidated the TBK1-regulated autocrine circuit that promotes the survival of KRAS-driven cancers, identified a small molecule TBK1/JAK inhibitor that inhibited the growth of KRAS-driven cancers in vivo, initiated a clinical trial involving the combination of this TBK1/JAK inhibitor with a clinically active MEK inhibitor, and identified mechanisms of resistance to KRAS-directed therapy. Based on the observation that oncogenic KRAS activates several pathways and transcriptional programs that conspire to drive cancer initiation and progression, we anticipate that combination strategies will be necessary to develop effective treatment regimens for KRAS- driven lung cancers. We propose to build on our preliminary studies to identify and credential complementary targets that will allow the development of rational combination therapies for KRAS-driven lung cancers. We will employ genetic, biochemical and pharmacologic approaches to eliminate c-RAF/MEK signaling, identify approaches to anticipate and target resistance mechanisms invoked by targeting KRAS effector pathways and develop combination therapies building on MEK and TBK1 inhibition. Specifically, we will use new technology to engender targeted degradation of c-RAF and MEK based on thalidomide-derivatized binders, and we will elucidate the role of, and develop therapies related to, the transcriptional regulators YAP1 and BRD4 in resistance to KRAS pathway inhibition. These studies will be performed in close collaboration with the other projects and cores of this Program and will inform the rational identification and development of effective combination therapies for KRAS-driven cancers.